Project Summary Glucocorticoids exert many effects in the central nervous system ranging from spatial learning and cognition to stress and depression. Interestingly, the effects of glucocorticoids upon neuronal circuits are also strongly influenced by neurotrophins, such as Brain Derived Neurotrophic Factor (BDNF). We have identified a novel pathway of communication between glucocorticoids and BDNF such that BDNF-signaling increased GR phosphorylation at serines 155 (S155) and 287 (S287). This altered the repertoire of genes controlled by GR, and disruption of the GR phosphorylation sites impaired neuroplasticity upon chronic stress. The goal of this proposal is to understand the physiological relevance of GR phosphorylation at S155 and S287 in neuroendocrine adaptation to stress in vivo using a newly developed GR phosphorylation-site-deficient (S155A/S287A) knock-in mouse, as well as the molecular mechanisms involved in phosphorylation-dependent regulation of GR-mediated gene expression. Our approaches include molecular, imaging and behavioral studies, genome wide assessment of GR target genes and receptor occupancy, as well as analysis of synaptic plasticity upon stress using two photon microscopy in the unique GR S155A/S287A knock-in mouse model. We will also examine whether GR pS155/pS287 is altered in PBMCs of depressed versus not depressed humans to lend relevance of this pathway to human behavior. Our studies will illuminate the genomic networks by which GR pS155/pS287 controls neuroendocrine adaptation to stress.